Building Nanoscale Structures with DNA

Erik Benson and Björn Högberg

The versatility of geometric shapes made from the nucleic acid are proving useful in a wide variety of fields from molecular computation to biology to medicine.

DNA—the biological information-storage unit and the mechanism by which traits are passed on from generation to generation—is more than just an essential molecule of life. In the chemical sense, the nucleic acid has properties that make it useful for nonbiological applications. Researchers are now using DNA to store massive amounts of data, for example, including books and images, a Shakespearean sonnet, and even a computer operating system, with data encoded in the molecule’s nucleotide sequences. At an even more fundamental level, DNA is a critical building block of nanoscale shapes and structures. Researchers have created myriad nanoscale objects and devices using the nucleic acid, with applications in biosensing, drug delivery, biomolecular analysis, and molecular computation, to name but a few. DNA provides a highly specific route to building nanostructures. While the field is still addressing how to scale up into the micrometer range, it is possible to imagine a future with DNA-based computer chips performing calculations and DNA nanobots delivering personalized medicine to target sites in the human body.

The straightforward and consistent pairing of DNA’s nucleotide bases make the molecule a reliable building material. Depending on the sequence, DNA strands can crossover to adjacent helices, creating a branch point. The four canonical nucleobases—adenine, guanine, thymine, and cytosine—are inherently programmable, as adenine always pairs with thymine, and guanine with cytosine. Just as these bases encode the biological instructions for building and maintaining an organism, so too do they form the basic code of designing shapes using DNA. Two strands that have complementary sequences of these nucleotides can bind to each other to form a double helix structure with a diameter of about 2 nanometers, and a single turn of DNA (a helical pitch) measuring about 3.4–3.6 nm. This helix is quite stiff within lengths of 15 helical pitches, or about 50 nm (its “persistence length”), allowing DNA to be used as a rigid construction material.

While entire chromosomes are composed of tightly coiled DNA, the double helix itself is inherently linear, extending in only one direction. For it to be useful for construction in two or three dimensions, branched DNA junctions are created by the reciprocal exchange of strands. This phenomenon occurs in nature—for example, during formation of the Holliday junction, an intermediate in genetic recombination. Synthetic DNA sequences can be designed to pair in certain ways, resulting in branched junctions with helices that extend in more than one direction. DNA can also hold other bits of DNA together: sticky ends, or short, single-stranded overhangs at the tips of a helical nucleic acid, can be designed to bind to one another by proper sequence complementarity. Such sticky ends act as structural glue to bind DNA motifs or complexes, resulting in hierarchical self-assembly of these macromolecules into larger arrays and larger complex architectures. (See illustration below.)

Crystallographer Ned Seeman, now at New York University, first proposed the idea of using DNA to build molecular scaffolds in the early 1980s. Seeman, then at the State University of New York at Albany, grew frustrated trying to crystallize molecules the traditional way, by exploring a range of experimental conditions by trial and error. He hypothesized that branched DNA could be used to build a framework to solve this crystallization problem by holding the molecule of interest in a defined spatial position, effectively crystallizing it. In 1983, he designed DNA sequences that formed stable, immobile, branched junctions containing four arms, which would lay the foundation for designing higher-order DNA structures and arrays, including a designed three-dimensional DNA crystal.